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Meta-Analysis
. 2016 Nov 29;13(11):e1002179.
doi: 10.1371/journal.pmed.1002179. eCollection 2016 Nov.

Genetic Predisposition to an Impaired Metabolism of the Branched-Chain Amino Acids and Risk of Type 2 Diabetes: A Mendelian Randomisation Analysis

Luca A Lotta  1 , Robert A Scott  1 , Stephen J Sharp  1 , Stephen Burgess  2 , Jian'an Luan  1 , Therese Tillin  3 , Amand F Schmidt  3 , Fumiaki Imamura  1 , Isobel D Stewart  1 , John R B Perry  1 , Luke Marney  4 , Albert Koulman  4 , Edward D Karoly  5 , Nita G Forouhi  1 , Rasmus J O Sjögren  6 , Erik Näslund  7 , Juleen R Zierath  6   8 , Anna Krook  8 , David B Savage  9 , Julian L Griffin  4   10 , Nishi Chaturvedi  3 , Aroon D Hingorani  3 , Kay-Tee Khaw  2 , Inês Barroso  9   11 , Mark I McCarthy  12 , Stephen O'Rahilly  9 , Nicholas J Wareham  1 , Claudia Langenberg  1
Affiliations
Meta-Analysis

Genetic Predisposition to an Impaired Metabolism of the Branched-Chain Amino Acids and Risk of Type 2 Diabetes: A Mendelian Randomisation Analysis

Luca A Lotta et al. PLoS Med. .

Abstract

Background: Higher circulating levels of the branched-chain amino acids (BCAAs; i.e., isoleucine, leucine, and valine) are strongly associated with higher type 2 diabetes risk, but it is not known whether this association is causal. We undertook large-scale human genetic analyses to address this question.

Methods and findings: Genome-wide studies of BCAA levels in 16,596 individuals revealed five genomic regions associated at genome-wide levels of significance (p < 5 × 10-8). The strongest signal was 21 kb upstream of the PPM1K gene (beta in standard deviations [SDs] of leucine per allele = 0.08, p = 3.9 × 10-25), encoding an activator of the mitochondrial branched-chain alpha-ketoacid dehydrogenase (BCKD) responsible for the rate-limiting step in BCAA catabolism. In another analysis, in up to 47,877 cases of type 2 diabetes and 267,694 controls, a genetically predicted difference of 1 SD in amino acid level was associated with an odds ratio for type 2 diabetes of 1.44 (95% CI 1.26-1.65, p = 9.5 × 10-8) for isoleucine, 1.85 (95% CI 1.41-2.42, p = 7.3 × 10-6) for leucine, and 1.54 (95% CI 1.28-1.84, p = 4.2 × 10-6) for valine. Estimates were highly consistent with those from prospective observational studies of the association between BCAA levels and incident type 2 diabetes in a meta-analysis of 1,992 cases and 4,319 non-cases. Metabolome-wide association analyses of BCAA-raising alleles revealed high specificity to the BCAA pathway and an accumulation of metabolites upstream of branched-chain alpha-ketoacid oxidation, consistent with reduced BCKD activity. Limitations of this study are that, while the association of genetic variants appeared highly specific, the possibility of pleiotropic associations cannot be entirely excluded. Similar to other complex phenotypes, genetic scores used in the study captured a limited proportion of the heritability in BCAA levels. Therefore, it is possible that only some of the mechanisms that increase BCAA levels or affect BCAA metabolism are implicated in type 2 diabetes.

Conclusions: Evidence from this large-scale human genetic and metabolomic study is consistent with a causal role of BCAA metabolism in the aetiology of type 2 diabetes.

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Conflict of interest statement

CL receives a stipend as a specialty consulting editor for PLOS Medicine and serves on the journal's editorial board. MIM is a member of the Editorial Board of PLOS Medicine. MIM is a member of advisory boards for NovoNordisk and Pfizer. MIM received honoraria for speaking engagements: NovoNordisk, Pfizer, Eli Lilly. MIM receives research funding from: NovoNordisk, Pfizer, Eli Lilly, Takeda, Servier, Sanofi-Aventis, Boehringer Ingelheim, Janssen, Merck, Roche, Astra-Zeneca. EDK is an employee of Metabolon Inc., a fee-for-service metabolomics provider and received salary and stock options as compensation. IB and her spouse own stock in GlaxoSmithKline and Incyte Corporation. SB acts as an occasional paid statistical referee for PLOS Medicine, however had no reviewer role in this paper. The other authors report no conflict of interest relative to this study.

Figures

Fig 1
Fig 1. Design of the study.
DIAGRAM, DIAbetes Genetics Replication And Meta-analysis.
Fig 2
Fig 2. Manhattan plot of the association of genetic variants with the levels of branched-chain amino acids.
Fig 3
Fig 3. Genetically predicted or measured levels of the branched-chain amino acids and risk of type 2 diabetes.
(A) Comparison of (i) the association of a difference of 1 SD in the levels of BCAAs at baseline with incident type 2 diabetes in prospective observational studies (bars with blue circles) and (ii) the association of a genetically predicted difference of 1 SD in BCAA levels with type 2 diabetes in genetic Mendelian randomisation studies (bars with red squares for analyses of independent genetic variants and bars with orange diamonds for analyses of correlated genetic variants). (B) Regional association plots for the association of variants at the PPM1K locus with valine (top; representative of the three BCAAs) and type 2 diabetes (bottom). Associations were characterised by a peak of signal upstream of the PPM1K gene, with the lead rs1440581 polymorphism and other polymorphisms in high linkage disequilibrium, as well as a peripheral signal overlaying the gene, with variants in lower linkage disequilibrium with the lead polymorphism. (C) Scatter plot of the association of the isoleucine-raising alleles included in the isoleucine genetic score with amino acid levels and with type 2 diabetes risk. (D) The association of the quartiles of isoleucine level at baseline with incident type 2 diabetes in the EPIC-Norfolk case-cohort study, the Framingham Offspring Study, and the Malmö Diet and Cancer Study (1,025 cases of incident type 2 diabetes and 1,182 controls). Error bars represent the 95% confidence intervals around the central estimates. BCAA, branched-chain amino acid; OR, odds ratio; RR, relative risk; SD, standard deviation; T2D, type 2 diabetes.
Fig 4
Fig 4. Association of branched-chain amino acid genetic scores with metabolites in the Fenland study.
Associations of the BCAA scores with the BCAAs are highlighted in dark red. Error bars represent the 95% confidence interval around the central estimate.BCAA, branched-chain amino acid; SD, standard deviation.
Fig 5
Fig 5. Schematic representation of the branched-chain amino acid pathway and associations with type 2 diabetes.
BCKD, branched-chain alpha-ketoacid dehydrogenase.
See this image and copyright information in PMC

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